DESCRIPTION (Applicant's abstract): Experimental and clinical observations suggest a functional crosstalk between the nervous and the immune system, largely mediated through shared ligands and receptors. Cytokines generated or gaining access to the CNS regulate the growth, survival, an d function of the CNS cells. Conversely, neuropeptides/ neurotransmitters released or produced within the lymphoid organs may regulate the function of immune cells. Previous studies reported in vitro immuno-modulation by neuropeptides. Several reports, including Dr Ganea's studies, indicate that some neuropeptides such as substance P stimulate immune functions, whereas other neuropeptides such as the vasoactive intestinal peptide (VIP) exert primarily an anti-inflammatory action. The in vitro anti-inflammatory role of VIP is supported by clinical data, which indicate an association of low VIP levels with highly reactive immune responses, and of high VIP levels with certain immunodeficiencies. Although several authors reported effects of VIP on immune responses little is known about the VIP immunomodulatory role in vivo, the regulation of VIP and VIP receptor expression in immune cells, and about the molecular mechanisms involved in VIP immunomodulation. Dr Ganea's studies indicate that VIP and the pituitary adenylate cyclase-activating polypeptide (PACAP), a recently discovered VIP-related neuropeptide, inhibit the production of selected cytokines such as IL-2 and IL-4 by unprimed CD4+ T cells stimulated in vitro through the T cell receptor. We hypothesize that antigenic stimulation upregulates VIP production and/or VIP receptor expression in vivo within the lymphoid organs, and that VIP/VIP-R interactions inhibit CD4+ T cell proliferation and cytokine production. In Specific Aim A we propose to examine whether antigenic stimulation induces VIP release in vivo, and whether antigen-stimulated CD4+ T cells function as VIP sources. In Specific Aim B we propose to study the regulation of VIP-R1 and VIP-R2 expression in antigen-stimulated CD4+ T cells and T cell lines, and the involvement of these receptors in mediating the inhibitory effect of VIP/PACAP on IL-2 production. In Specific Aim C we propose to investigate the nature of the VIP cellular targets, and the molecular mechanisms, including the transduction pathways and transcriptional factors involved in the inhibitory effect of VIP/PACAP on IL-2 gene expression. The establishment of VIP and related neuropeptides as active participants in limiting a normal immune response and therefore preventing excessive tissue damage, and the elucidation of the molecular mechanisms involved, could have significant therapeutical consequences, particularly in autoimmune diseases.